The present invention relates to novel inhibitory peptides and, more particularly, to short peptides which inhibit .alpha..sub.2 .beta..sub.1 -mediated Mg.sup.++ -dependent adhesion of platelets.
The .alpha..sub.2 .beta..sub.1 integrin is electrophoretically and immunochemically identical to the platelet membrane glycoprotein Ia-IIa complex, the very late activation antigen 2 (VLA-2) on T cells, and the class II extracellular matrix receptor (ECMRII) on fibroblastic cells (1-6). The heterodimeric receptor which is composed of 160 kDa and 130 kDa polypeptides was initially characterized as a mediator of Mg.sup.++ -dependent cell adhesion to collagen (2,3,5,7-9). Recent findings indicate that whereas on platelets and fibroblasts the .alpha..sub.2 .beta..sub.1 integrin serves as a collagen-specific receptor, on other cells, such as endothelial cells or melanoma cell lines, the .alpha..sub.2 .beta..sub.1 integrin may exhibit a broader specificity and function as both a collagen and laminin receptor (10-13).
Several integrins, including the platelet IIb-IIIa complex (.alpha..sub.IIb .beta..sub.3), the vitronectin receptor (.alpha..sub.v .beta..sub.3) and the fibronectin receptor (.alpha..sub.5 .beta..sub.1), recognize an arg-gly-asp (RGD) sequence within their adhesive protein ligands (14,15). The .alpha..sub.4 .beta..sub.1 integrin serves as a fibronectin receptor on lymphoid cells, but recognizes a relatively short linear sequence of amino acids which does not contain the RGD sequence (16-18).
Although RGD sequences are present in collagen molecules, two lines of evidence suggest that RGD does not serve as a recognition sequence on collagen for the .alpha..sub.2 .beta..sub.1 integrin. First, Mg.sup.++ -dependent platelet adhesion to collagen mediated by the .alpha..sub.2 .beta..sub.1 integrin is not inhibited by peptides containing RGD sequences (7). Second, it was recently demonstrated that the .alpha..sub.2 .beta..sub.1 integrin binds to the .alpha.1(I)-CB3 fragment of collagen which does not contain an RGD sequence (19).